This research involves a comprehensive study of the mechanisms of differentiation and development and the action of thyroid hormone using amphibian metamorphosis as a model system. Particular attention is paid to the initiating mechanisms by which thyroid hormones trigger the metamorphic process. This includes a study of thyroid hormone receptors and effects on genetic expression originating in cell nuclei. We also hope to contribute to knowledge of comparative biochemistry, endocrinology, embryonic development and biochemical evolution. Emphasis will be placed on three objectives: (1) Studies on the properties of the nuclear receptors of the thyroid hormone in anurans will be continued. This includes the study of the effect of temperature, subcellular distribution and the question of cytoplasmic binding of T3 and T4, the binding of T3 to tadpole chromatin, and the isolation and characterization of nuclear-T3 binding proteins. Relationships to the onset and completion of metamorphosis, specific tissue response, and finally, to hormonal states in other amphibian systems will be sought. (2) To find out what the thyroid hormone does in the nucleus, we will concentrate on changes in macromolecular biosynthesis during spontaneous and induced metamorphosis. This will include an analysis of alterations in mRNA biosynthesis and processing, possible effects on mitochondrial DNA, RNA and protein, and changes in the rates of protein synthesis and degradation during metamorphosis. (3) Finally, we propose to use all these ideas and results to determine the basis of endocrine control of developmental blocks in other amphibia. The urodeles provide a rich reservoir of biological systems, frequently incomplete in their endocrine mechanisms and developmental expressions. Thus we hope to answer many basic questions on the underlying endrocrine mechanisms which have evolved to reach the present state of vertebrate endocrinology.